Toxicology Challenges in Lifestage- Specific Safety ...2. Subpopulation Assessment at CFSAN-Food...
Transcript of Toxicology Challenges in Lifestage- Specific Safety ...2. Subpopulation Assessment at CFSAN-Food...
Toxicology Challenges in Lifestage-Specific Safety Assessments
April Neal Kluever US FDA/CFSAN/OFAS/DFCN [email protected]
Conflict of Interest Statement
Dr. Kluever does not have any conflicts of interest
Toxicology Challenges in Lifestage-Specific Safety Assessments
April Neal Kluever, PhD, DABT Toxicologist Food and Drug Administration Center for Food Safety and Applied Nutrition Office of Food Additive Safety Division of Food Contact Notifications
Disclaimer
The data and interpretations expressed in this presentation represent that of the author and not necessarily that of the US FDA
Outline
1. Background and Definitions 2. Subpopulation Assessment at CFSAN-Food
Advisory Committee Recommendations 3. Infants as a case example for lifestage safety
assessment 4. Challenges in Infant Safety Assessment 5. Summary
Background and Definitions
US FDA Center of Food Safety and Applied Nutrition
Mission: promoting and protecting the public's health by ensuring that the nation's food supply is safe, sanitary, wholesome, and honestly labeled, and that cosmetic products are safe and properly labeled. • Covers all domestic and imported food except meat, poultry,
and frozen, dried, and liquid eggs. • Covers all domestic and imported cosmetics.
Definitions- What are Subpopulations?
Divisions of the general population on the basis of some discriminating factor/s
• Age (infant, toddler, child, adolescent, adult, elder) • Physiological state (pregnancy) • Disease state (diabetes)
Definitions- What are Lifestages?
A lifestage is defined as a temporal stage of life that has distinct anatomical, physiological, and behavioral or functional characteristics that may contribute to different susceptibility to chemical exposures compared to the general population (Makris et al., 2008)
Definitions- What are Lifestages?
“Where a statute might use the term ‘subpopulation,’ EPA recognizes this as including consideration of age groups or life stages.” • Life stages are a type of subpopulation
US EPA (2014). Framework for Human Health Risk Assessment to Inform Decision Making https://www.epa.gov/sites/production/files/2014-12/documents/hhra-framework-final-2014.pdf
Outline: 1. Background and Definitions 2. Subpopulation Assessment at CFSAN-Food
Advisory Committee Recommendations 3. Infants as a case example for lifestage safety
assessment 4. Challenges in Infant Safety Assessment 5. Summary
2014 Food Advisory Committee (FAC) Meeting
CFSAN requested advice from the FAC on how to integrate scientific considerations for susceptible populations into its risk assessment procedures and methodologies
• Proceedings and resource materials published online: http://www.fda.gov/AdvisoryCommittees/CommitteesMeetingMaterials/FoodAdvisoryCommittee/ucm407113.htm http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/FoodAdvisoryCommittee/UCM428847.pdf
FAC on Susceptible Populations Key Recommendations
A separate risk (or safety) assessment may be conducted when there is 1. A clearly bi- or multi-modal distribution to the
functioning of an influential enzyme or system such that the expected risks will be distinct.
FAC on Susceptible Populations Key Recommendations
A separate risk (or safety) assessment may be conducted when 2. A lifestage appears vulnerable based upon critical
windows of toxicokinetic immaturity or toxicodynamic sensitivity and this sensitivity has been characterized in dose response studies.
FAC on Susceptible Populations Key Recommendations
A separate risk (or safety) assessment may be conducted when there is 3. A subgroup or lifestage that will receive a disproportionally high exposure to a food, product, or environmental media that contains toxicants that are of particular concern to the subgroup or lifestage.
Outline
1. Background and Definitions 2. Subpopulation Assessment at CFSAN-Food
Advisory Committee Recommendations 3. Infants as a case example for lifestage safety
assessment 4. Challenges in Infant Safety Assessment 5. Summary
Infants as an Example for Lifestage-Specific Safety Assessment
Infant Safety Assessment at CFSAN: Lifestage-specific
Infant-specific safety assessments are performed for food contact materials intended for use with breast milk or infant formula Lifestage-specific safety or risk assessments may also be performed for other programmatic areas in CFSAN
Infants Experience a Different Exposure Scenario than other Lifestages
• Increased food consumption compared to other age groups (mg/kg-bw/d)
• Restricted variety of food products – May consume a sole source of nutrition for up to 6
months (breast milk or infant formula) – Do not exhibit the same food consumer patterns as other
age groups
Lawrie, 1998; National Research Council, 1993; Neal-Kluever et al, 2014
Recommendation for Subpopulation Assessment from the CFSAN FAC
A separate risk (or safety) assessment may be conducted when there is: 1. A clearly bi- or multi-modal distribution to the functioning of an
influential enzyme or system such that the expected risks will be distinct;
2. A lifestage appears vulnerable based upon critical windows of toxicokinetic immaturity or toxicodynamic sensitivity and this sensitivity has been characterized in dose response studies;
3. There is a subgroup or lifestage that will receive a disproportionally high exposure to a food, product, or environmental media that contains toxicants that are of particular concern to the subgroup or lifestage.
Potential for Altered Exposure Scenario Occurs during Period of Development
Developing Systems: • Reproductive • Endocrine • Neurological • Skeletal • Immunological
Developing Physiology: • Absorption • Distribution • Metabolism • Excretion
For in-depth reviews, see Neal-Kluever et al, 2014, Food and Chem. Toxicol. 70: 68-83 Felter et al, 2015, Crit. Rev. Toxicol. 43:219-244
Developing Physiology: Infant Pharmacokinetics (or Toxicokinetics)
Toxicokinetics are about processes Infants exhibit altered absorption, distribution,
metabolism, excretion, and storage of some chemicals compared to other lifestages – Rapid changes in the first 6 months after birth
Altered PK/TK can have a large impact on the toxicity of a chemical and infant susceptibility
Examples of Altered Toxicokinetics
23
Chemical Relative to Adult
Determinants References
Dioxins Faster elimination Lower body fat in infants
Kreuzer et al, 1997
Methylated Xanthines
Slower elimination Deficient CYP1A2 Ginsberg, 2004
Developing Systems: Infant Pharmacodynamics (or Toxicodynamics)
• Toxicodynamics are about biological targets • Infants may express more or less of the biological
targets of a chemical than other lifestages
Examples: • Receptor ontogeny • High cellular turnover (increased targets for
carcinogens)
Recommendation for a Subpopulation Assessment
A separate risk (or safety) assessment may be conducted when there is: 1) A clearly bi- or multi-modal distribution to the functioning
of an influential enzyme or system such that the expected risks will be distinct;
2) A lifestage appears vulnerable based upon critical windows of toxicokinetic immaturity or toxicodynamic sensitivity and this sensitivity has been characterized in dose response studies;
3) There is a subgroup or life stage that will receive a disproportionally high exposure to a food, product, or environmental media that contains toxicants that are of particular concern to the subgroup or lifestage.
Steps in Infant Lifestage Assessment
1. Estimation of infant-specific exposure to substance of interest
• Consideration of infant-specific factors such as weight, intake, and consumer habits
2. Safety or risk assessment in an infant-specific context
Outline
1. Background and Definitions 2. Subpopulation Assessment at CFSAN- Food
Advisory Committee Recommendations 3. Infants as a case example for lifestage safety
assessment 4. Challenges in Infant Safety Assessment 5. Summary
Challenges in Infant Safety Assessment
1. When to test? 2. What to test? 3. How to test? 4. How to interpret the data?
Challenges: When to Test?
The FAC provided guidance regarding when a separate safety assessment should be performed. It remains an expert decision to determine when
additional or specialized toxicological testing is needed to support infant safety
Challenges: What to Test?
What are some ways to identify or prioritize chemicals for specialized testing?
• Public literature, Tox21, screening assays, in silico prediction approaches, other hazard identification tools.
Challenges: How to Test?
Which study design can best characterize potential hazards for human infants? Developmental and Reproductive Toxicity (DART) Tests Generational developmental and reproductive testing Prenatal toxicity testing Perinatal/Postnatal toxicity testing Other specialized juvenile animal test protocols
Addressing Challenges in Study Selection
Should a large study that captures many endpoints be recommended to support infant safety, or should a smaller and targeted study be recommended?
Addressing Challenges in Study Selection: CFSAN Initiatives
Assessment of the utility of generational developmental and reproductive toxicity (Gen-DART) testing for infant safety assessment Ongoing regulatory research initialized Sept, 2014 Completed analysis of 40 Gen-DART studies on 37 food
additives Current efforts underway to expand the study library by
harnessing data from exterior sources (ToxRefDB, NTP reports, etc)
The Gen-DART Project
Addressing Challenges in Study Selection: CFSAN Initiatives
Assessment of the utility of juvenile animal study (JAS) protocols for infant safety assessment Collaborative effort with the US FDA Center for Drug
Evaluation and Research (CDER) Research initiated in Nov. 2015 Pilot capture of data associated with 60 drugs is underway
The JAS Project
Addressing Challenges in Study Selection
Ongoing regulatory research will provide scientific framework for the recommendation of specific study protocols to support infant safety
This research may also inform questions on interpretation of study data and extrapolation of potential hazards from the test species to human infants
Challenges: How to Interpret the Data?
Nearly all DART study designs have several major areas of uncertainty 1. Uncertainty regarding test article exposure to pups
OECD Test No 443: Extended One-Generation Study
http://www.oecd-ilibrary.org/docserver/download/9712211e.pdf?expires=1459362714&id=id&accname=guest&checksum=A4F898CA316F8106C46FE9AB2259A0E5
Pups are not directly exposed to the test article until weaning in most generational studies
How to Address Uncertainty Regarding Test Article Exposure to Pups
1. Direct dosing of pups in DART studies (e.g. oral gavage)
2. Toxicokinetic profiling of chemicals to be tested in DART studies
3. Physiologically-based pharmacokinetic (PBPK) modeling
Challenges: How to Interpret the Data?
Nearly all DART study designs have several major areas of uncertainty 1. Uncertainty regarding test article exposure to pups 2. Uncertainty regarding test model selection
– All currently validated regulatory test protocols use mice, rats, or rabbits to test for developmental effects.
Species Exhibit Differences in Developmental Trajectories
Zoetis T and ME Hurtt (2003). Birth Defects Res B 68:111-120
Kidney Development
How to Address Uncertainty Regarding Species Extrapolation?
1. Examination of human data, if available 2. PBPK modeling 3. Development or validation of additional models or
test systems
Summary
Infants fulfill the CFSAN FAC criteria as a lifestage of interest.
Infant-specific exposure and safety assessments can be performed if relevant data are available.
Infant lifestage-specific assessment is an emerging field of regulatory research.
Regulatory research efforts are underway to optimize the approach to infant safety assessment.
References
Felter et al., 2015. Crit. Rev. Toxicol. 43:219-244 Ginsberg et al, 2004. J Toxicol Environ Health (A). 67:297-329 Kreuzer et al, 1997. Arch Toxicol. 71: 383-400 Lawrie, C.A., 1998. Food Addit. Contam. 15:75–81 Makris SL, et al., 2008. Birth Defects Res. B 83:530-546. National Research Council, 1993. Pesticides in the Diets of Infants and Children. National Academy Press, Washington, DC. Neal-Kluever et al., 2014. Food and Chem. Toxicol. 70: 68-83 Zoetis, T. and Hurtt, M.E., 2003. Birth Defects Res. B 68:111–120.